Comparison of monocyte distribution width and Procalcitonin as diagnostic markers for sepsis: Meta-analysis of diagnostic test accuracy studies

Aim We aimed to perform a meta-analysis to find out whether PCT and MDW could be used as accurate diagnostic markers for sepsis. Methods We searched PUBMED, WOS, and SCOPUS databases. Inclusion criteria were any observational or clinical trials that compared monocyte Distribution Width [MDW] with Procalcitonin [PCT] as diagnostic markers in a patient with sepsis. Case reports, editorials, conference abstracts, and animal studies were excluded. RevMan software [5.4] was used to perform the meta-analysis. Results After the complete screening, 5 observational studies were included in the meta-analysis. The total number of patients included in the meta-analysis in the sepsis group is 565 and 781 in the control group. The pooled analysis between the sepsis group and controls showed a statistically significant association between sepsis and increased levels of MDW and PCT [MD = 3.94, 95% CI = 2.53 to 5.36, p-value < 0.00001] and [MD = 9.29, 95% CI = 0.67 to 17.91, p-value = 0.03] respectively. Moreover, the subgroup analysis showed that the p-value of MDW levels [< 0.00001] is more significant than the p-value of PCT levels = 0.03, the p-value between the two subgroups [< 0.00001]. Additionally, the overall ROC Area for MDW [0.790] > the overall ROC Area for PCT [0.760]. Conclusion Our study revealed a statistically significant association between sepsis and increased MDW and PCT levels compared with controls and the overall ROC Area for MDW is higher than the overall ROC Area for PCT, indicating that the diagnostic accuracy of MDW is higher than PCT.MDW can be used as a diagnostic marker for sepsis patients in the emergency department. More multicenter studies are needed to support our findings.


Introduction
Sepsis is a potentially fatal organ failure occurred by an inadequate host defense against infection [1,2]. A systemic inflammatory reaction is how sepsis is typically described. In sepsis, the natural balance between pro-and anti-inflammatory activities becomes disrupted. Localized tissue reaction to infection becomes systemic, and the inflammatory process becomes itself becomes harmful [3]. It has three states: sepsis, severe sepsis, and septic shock, all of which advance with increasing severity [2]. Sepsis is one of the leading causes of mortality in intensive care units [ICUs] [4,5]. Sepsis incidence rates are increasing, reaching 535 cases per 100,000 person-years [6]. Hospital mortality is still very high, at 25 to 30 percent [6].
Various biomarker subtypes have been identified based on their alleged applicability. Importantly, a single biomarker might fulfill several criteria for different applications, but it is crucial to establish a reliable justification for each explanation [7]. For instance, biomarkers based on monocytes are found to be involved in numerous inflammatory disorders. According to Tel et al, [8] type 2 diabetes mellitus patients in the frail and non-frail groups had significantly different monocyte lymphocyte ratio [MLR] levels during COVID-19. Frail individuals' values were noticeably greater than those of non-frail diabetics. MLR could therefore be used as a dependable and prognostic indicator of frailty [8]. Kocak et al. [9] measured the MRL in patients with diabetic kidney injury [DKI]. Two groups of T2DM patients-those with microalbuminuria [MA] and those with normoalbuminuria [NA]-were created. They stated that MLR and MA showed a statistically significant association. Thus, given its great association with MA, low cost, and availability, MLR might function as a predictive and efficient marker for DKI in diabetic people [9]. MRL was also investigated in the context of Covid-19 infection. According to reports, MLR increased in Covid-19 infection patients compared to healthy controls. To anticipate the disease, its severity, and the mortality of Covid-19 infection, MLR is a useful technique [10]. In patients with sepsis, different biomarkers have been investigated for application in infection identification, prognostication, and therapy guidance [11]. Sepsis biomarkers might offer information that isn't available through other parameters, this could help guide clinical decision-making and possibly enhance patient care. If the biomarkers that could precisely diagnose sepsis early were available, antibiotic therapy might be provided more promptly and appropriately and superfluous medications could be avoided. Similarly, biomarkers could assist healthcare providers in evaluating the effectiveness of their therapeutic decisions and modifying the treatment as necessary [12]. Numerous possible sepsis biomarkers have been presented. In particular, procalcitonin [PCT], C-reactive protein [CRP], white blood cells [WBC], erythrocyte sedimentation rate [ESR], and different interleukins have been used as diagnostic biomarkers for SIRS, sepsis, and severe sepsis [13]. The clinical application of PCT and biomarkers is controversial. Yet, prior research found that PCT could support patient clinical diagnosis and care. Among these biomarkers, Surviving Sepsis Campaign 2013's diagnostic standards for inflammatory variables includes PCT and CRP [13]. Above all, early data on the potential importance of monocyte distribution width [MDW] were gathered [14], when activated in bacteremia patients, monocytes have been found to enlarge, and this infection-related size change can be easily observed by monitoring the distribution of monocytes in coulter chambers [14]. On the first visit, sepsis is frequently overlooked. Herein lies the value of MDW, whose results can be obtained sooner compared to those of other biomarkers. This offers a crucial study avenue to evaluate incorporating MDW within current routine WBC counts for sepsis detection [15]. Different results have been reported for the accuracy of PCT and MDW as diagnostic markers for sepsis, so we aimed to perform a meta-analysis to find out which one of them could be used as the accurate diagnostic marker for sepsis.

Methods
This meta-analysis was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses [PRISMA] guidelines and the Cochrane handbook [16].
We searched PUBMED, Web of Science, and SCOPUS from inception to May 1, 2022. We used the following key terms;[["Monocyte Distribution Width"] OR ["Procalcitonin" or "Calcitonin Precursor Polyprotein" or "Calcitonin-1" or "Calcitonin Related Polypeptide Alpha"] AND ["Recognition of Sepsis"]]. We further reviewed the list of references of studies included in this meta-analysis to include other relevant studies. The studies were eligible for inclusion if they met the following criteria:

Screening, data extraction, and risk of bias
Two reviewers [S.R and P.C] conducted initial title and abstract screening and all conflicts were discussed to reach an agreement, otherwise, a third opinion from [K.R.M] was obtained.
Potentially eligible articles were imported for full-text screening and assessed for inclusion. Data were extracted using an Excel sheet. Examples of data collected are study arms, number of patients in each group, age, sex [n], other baseline diseases, and baseline treatment.
We used the New Castle Ottawa Scale [NOS] tool to assess the quality of the included observational studies. Each study was ranked as; good, fair, or poor quality.

Data analysis
Review Manager Software version 5.4 was used to perform the meta-analysis; the continuous outcomes were presented as mean difference [MD] with a 95% confidence interval. If heterogeneity was detected [Chi-square P value < 0.05], a random effect model was used otherwise, we used a fixed-effect model, in general; the results were considered significant if the P-value was less than 0.05. MedCalc software was used to calculate the overall AUC for MDW and PCT.

Literature search
After a comprehensive search of the literature, 768 studies resulted, and then became 663 were eligible for the title and abstract screening after the removal of duplicates. Of the 663, 654 were irrelevant and 9 studies were eligible for full-text screening. Finally, 5 observational studies were included in the meta-analysis after the full-text screening, as shown in the PRISMA in [Fig 1], summary of the included study is shown in Table 1.
MDW and PCT overall levels, MDW overall [AUC], and PCT overall [AUC] outcomes were compared between the sepsis group and control group. The overall quality was high in the included 5 studies as shown in Table 2.
The total number of patients included in the study is 1346 patients, 565 patients in the sepsis group, and 781 patients in the control group, other baseline data are shown in Table 3.

Outcomes MDW and PCT overall levels.
The pooled analysis showed a statistically significant association between sepsis and increased levels of MDW compared with controls [MD = 3.94, 95%  In conclusion, MDW is a more sensitive biomarker than PCT in predicting infection-related SIRS and sepsis-3 in the ED. MDW<20 shows a higher NPV to exclude sepsis-3. Combining MDW and WBC count further improves the accuracy in predicting infection with SIRS but not sepsis-3.

Woo 2021
Prospective cohort study  Table 3. Baseline characteristics of the included data.

PLOS ONE
The subgroup analysis showed that the p-value of MDW levels [< 0.00001] is more significant than the p-value of PCT levels = 0.03, the p-value between the two subgroups [< 0.00001]. We observed no significant heterogeneity between the two subgroups [pvalue = 0. 23

Discussion
Our meta-analysis showed a statistically significant association between sepsis and increased MDW and PCT levels compared with controls, the subgroup analysis showed that the p-value of MDW is more significant than the p-value of PCT in sepsis diagnosis, another analysis showed that the overall ROC Area for MDW is higher than the overall ROC Area for PCT, indicating that the diagnostic accuracy of MDW is higher than PCT.
The multiple test analysis showed that the pooled ROC Area for [MDW >20] > the ROC areas of the [MDW >22] and [MDW >20].
Blood culture is a crucial diagnostic tool for sepsis because it may be used to identify pathogenic bacteria and test for antibiotic sensitivity, however it's time-consuming and prone to false-negative results, especially after antibiotic usage [17]. According to statistics, people with sepsis have a survival rate of more than 80% if they are accurately diagnosed and treated within 1 hour of infection, however this number reduces to 30% if they receive treatment after 6 hours [18]. Finding a biomarker for the early detection of sepsis is therefore essential. The molecules indicating changes in immunoinflammatory state, such as PCT and MDW, appear to be promising among the several sepsis biomarkers explored so far [19,20].

PLOS ONE
PCT, which is produced by C cells in the thyroid gland and, to a lesser extent, other neuroendocrine cells all throughout the body, is a precursor to the hormone calcitonin [21]. In very early stages of fetal development, it is also expressed in the central nervous system [22]. With a half-life of roughly 20-24 h, PCT is an extremely stable protein both in vitro and in vivo [23,24]. Serum PCT levels in healthy people are typically very low [0.02 ng/mL] [18]. There are, however, two primary pathways to PCT production in the context of bacterial infection: the direct pathway, induced by LPS or other harmful microbial metabolites [25], and the indirect pathway, induced by proinflammatory cytokines [TNF-, IL-1, and IL-6] that cause the expression of CALC-1, the gene responsible for PCT production, in numerous cells all over the body [22]. Because PCT cannot be converted to calcitonin, it reaches the circulation system where its levels can quickly rise by more than 400 times [> 4.0 ng/mL] over baseline values [26]. Moreover, PCT should be consistently produced in both immunocompetent and immunocompromised patients because it is produced by tissues in the setting of bacterial infection in addition to immune cells [22]. Furthermore, in that study, PCT performed better as a diagnostic biomarker for sepsis than C-reactive protein [CRP], IL-6, and lactate [27].
MDW, a hematologic parameter which is assessed as part of the complete blood count with differential [CBC-DIFF] [28], and measures the dispersion around the mean of the monocyte volume population in whole blood, could be an early indicator of infection and sepsis, according to some studies [14,[29][30][31][32][33]. MDW can be used to measure monocyte activity and morphological alterations during the early inflammatory response [32]. MDW role in sepsis detection in the ED first investigated by Crouser et al., demonstrating that MDW enhanced initial sepsis detection [32]. In our meta-analysis, we contrasted MDW with PCT, the most prevalent inflammatory biomarker used to detect sepsis.
Li et al compared MDW against PCT as diagnostic markers for sepsis patients, when they used 20 as the MDW cut-off value, significantly higher sensitivity and NPV were noticed with MDW than PCT at 0.5 ng/mL as the cut-off value. Also, at the MDW cut-off value of 20, an excellent negative prognostic value for sepsis exclusion was revealed. The Overall results showed that MDW had better predictive value in both early sepsis screening and patient outcome [34].
Woo et al compared MDW against PCT and CRP as diagnostic markers for sepsis patients, MDW revealed a higher sensitivity than other markers at optimal cutoff from the cohort

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which is explained by the rapid response of monocyte to infection. The analysis also showed that MDW revealed a significantly higher diagnostic accuracy in terms of AUC in the overall population by adding clinical score [qSOFA], in contrast to adding tests for CRP and PCT which do not show advantages in diagnosis of sepsis [35].
Polilli et al compared MDW against PCT as diagnostic markers for sepsis patients, they found that the MDW cutoff of 21.9 was shown to be the most accurate threshold for sepsis prediction, so for sepsis prediction, MDW at >22 was extremely sensitive and specific. They also found that Low MDW values may be a useful tool to rule out bloodstream infections because they had a very high NPV for sepsis and a 100% NPV for bacteremia at MDW values <20 which could be used to rule out sepsis in routine blood counts [14]. Polilli et al 2021 compared   [36]. Our results agree with the results of Pollilio 2020 and Polillio 2021 which reported that MDW>20 has more sensitivity and specificity and has more diagnostic value than other levels [14,36].
One explanation for the enhanced sensitivity of MDW in the sepsis diagnosis may be the fact that monocyte differentiation in the circulation starts relatively early in the sepsis cascade. One of the limitations of MDW is that in patients with a monocyte event <100 count in the peripheral blood sample, the MDW value is not available [34]. Clinically it is difficult to exclude critical patients using PCT as PCT was found to be a specific but not a sensitive biomarker in terms of sepsis-3 prediction [37, 38]. The results of our study can be used in clinical practice by depending on MDW more than PCT as a diagnostic marker in sepsis patients and MDW>20 should be considered the cut-off value for the diagnosis of sepsis in intensive care units. Our study is strengthened by the high sample size [1346 patients], the overall quality was good in all 5 included studies, also it is the first met analysis of diagnostic test accuracy studies to compare the diagnostic accuracy of MDW against PCT for sepsis, we also compared the accuracy of the two diagnostic markers in the same patients. However, our study is limited by the detected heterogeneity among studies but the overall heterogeneity between MDW and PCT subgroups was not significant.

Future implications
Our analysis results revealed that PCT and MDW can be used as diagnostic markers for sepsis detection, with higher diagnostic accuracy of MDW than PCT. Additionally, MDW cut-off value of 20, can be used as an excellent negative prognostic value for sepsis exclusion.

Conclusion
Our study revealed a statistically significant association between sepsis and increased MDW and PCT levels compared with controls and the overall ROC Area for MDW is higher than the overall ROC Area for PCT, indicating that the diagnostic accuracy of MDW is higher than PCT. MDW markers with a cut-off value > 20 could be used as diagnostic markers of sepsis patients in the emergency department. More multicenter studies are needed to support our findings.